基于单克隆抗体的靶向治疗极大地改善了肿瘤患者的治疗选择。近年来，蛋白质工程技术的进步推动着双特异性抗体（BsAbs）药物的问世，也代表着抗体构建体使用的范例转变。BsAbs以更高的治疗应答和耐药屏障、更少的不良反应已备受学界瞩目，而下一代“双特异性或多特异性抗体”的浪潮也将迎面扑来。在第50届欧洲血液和骨髓移植学会（EBMT）年会上，来自葡萄牙肿瘤研究所的Maria Gomes Da Silva 教授针对BsAbs治疗淋巴瘤的最新进展做了精彩报告。《血液时讯》特邀请Da Silva教授走进现场会客室，和广大读者分享该领域的最新进展和挑战。
《肿瘤瞭望-血液时讯》:近年来，BsAbs在治疗B细胞性非霍奇金淋巴瘤(B-NHL)领域显示出巨大潜力。请您为我们介绍一下该种药物的独特作用机制及其优势？
Da Silva教授：近年来，BsAbs在治疗B-NHL领域成为研究的热点。它们的“双特异性”指的是它们能同时识别并结合到两种不同的分子上，其中一种为广泛存在于肿瘤细胞表面的分子（如CD20），另一种为人体免疫系统的T细胞上的分子（如CD3）。BsAbs通过这种独特的机制，能够将T细胞和肿瘤细胞拉到一起，同时激活T细胞对肿瘤细胞的攻击。这就是BsAbs的作用机制。
We are dealing with antibodies engineered to express a dual specificity. In the case of B-cell lymphomas one of them is a B cell surface antigen, most commonly CD20. The other one is an antigen of an immune cell, mostly CD3 in T-cells. When the antibody binds the T cell it will activate it through CD3 in a way that is not restricted by MHC Class I, which is important because many of the aggressive malignancies do not express it. At the same time, they bring the lymphoma cell and the T-cell into close proximity, promoting the formation of an immune synapse and cytotoxicity from the T-cell against the B-cell. Many cytokines can be produced that can help with the amplification of the immune response, and recruitment of more T-cells. So this is the main mechanism. What is happening is that we are harnessing the patient’s immune system to destroy the lymphoma cells. In a general way, this is the mechanism.
《肿瘤瞭望-血液时讯》:请您分享一下，近年来BsAbs在淋巴瘤治疗中的最新临床研究成果？
Da Silva教授：的确，BsAbs在B-NHL的治疗方面涌现出很多最新进展。在本届大会上，我向大家主要介绍了在弥漫性大B细胞淋巴瘤（DLBCL）和滤泡性淋巴瘤方面的主要成果。前者是一种常见的侵袭性亚型，后者是一种惰性亚型。其他类型的淋巴瘤也有结果，包括套细胞淋巴瘤，但由于时间限制，不可能涵盖所有内容。关于B细胞淋巴瘤，我们在欧洲和美国现在有一种产品被批准用于滤泡性淋巴瘤，即莫舒妥珠单抗（Mosunetuzumab）；两种产品获得批准用于治疗DLBCL，一个是格菲妥单抗（Glofitamab)，是一种静脉注射的用药，另一个是艾可瑞妥单抗（Epcoritamab），为皮下给药。导致这两种药物批准的临床试验纳入了相似数量的患者，在最近一次ASH会议上公布的结果中，两种药物在18-20个月的随访时间里，取得的总体反应率为50%-60%，完全缓解率约为40%。并且在获得完全应答的患者中，均维持了持久的应答。尤其是格菲妥单抗的临床研究显示，有大约三分之二的获得完全缓解的患者，他们在18个月的随访中维持了这种完全缓解。目前这两项临床研究仍在进行中，随着时间的推移我们也会看到更多的进展。另一方面，我们还看到了单克隆抗体与化疗或其他免疫疗法、抗体-药物偶联物的联合治疗的许多进展，取得了初步的研究成果。
Mosunetuzumab在侵袭性亚型中作为单一疗法似乎不太有效，但在滤泡性淋巴瘤中它实现了高应答率和完全缓解率（约60%），并且它的完全缓解可以相当持久。我们必须考虑到滤泡性淋巴瘤的异质性非常高，患者经过化疗后将面临耐药的情况，尤其在二线或三线治疗时，目前仍没有一个标准化的选择。因此，BsAbs的双特异性可能是一种非常有吸引力的选择。
无论是DLBCL，还是滤泡性淋巴瘤，目前我们还不能实现治愈。但是随着进一步的随访研究，我们会更好地了解BsAbs的治疗潜力。此外，BsAbs还有一些优点，我们倾向于将它们与CAR-T细胞的结果进行比较。相比之下，BsAbs双特异性治疗更加便捷，它们作为一种现成的药物我们不需要预处理或等待细胞产品的制备。对于无法等待的患者来说，这可能是一个更具吸引力的选择。也许在未来，BsAbs可能作为CAR-T细胞治疗的桥梁。然而目前，我们更倾向于先在候选患者中使用CAR-T细胞治疗，然后在肿瘤复发的情况下用BsAbs进行挽救治疗。我们已经开展了相关的临床试验，使用BsAbs作为侵袭性淋巴瘤患者CAR-T治疗后的维持治疗。
I think we have new updates pretty much every meeting. During my presentation, I tried to focus on diffuse large B-cell lymphoma, an aggressive and common subtype, and follicular lymphoma, an indolent subtype. There are results in other types of lymphomas, including mantle cell lymphoma, but due to time constraints it is not possible to cover everything. Regarding B-cell lymphoma, we have in Europe and the US now one product approved for follicular lymphoma (mosunetuzumab) and two products approved for diffuse large B cell lymphoma- glofitamab, which is administered IV for a limited duration of 12 cycles (a little over 8 months); and epcoritamab, which is administered subcutaneously until progression. The trials that led to the approvals of these two antibodies were not comparative, included a similar number of patients, and at this time, share quite similar follow-ups of 18-20 months. What we are seeing is an overall response rate of 50-60%, and a complete response of about 40% for both agents in diffuse large B cell lymphoma. Both translate into very durable responses in complete responders. If you look at the glofitamab results, about two-thirds of the patients that are in complete response maintain this complete response at 18 months follow-up. If you look at epcoritamab at 20 months median follow-up, you have a median 21 months duration of complete response. These trials are still ongoing, so we will probably see more developments. We are also seeing a lot of developments in terms of combinations of these monoclonals with many different agents including chemotherapy, other immunotherapies and antibody drug conjugates. Some of those have results but they are still preliminary. For the time being, there has been approval of these two antibodies for the aggressive subtypes. Mosunetuzumab, in contrast, was approved for follicular lymphoma. Mosunetuzumab seems less effective as monotherapy in the aggressive subtypes, but it achieves high response rate and complete responses (around 60%) in follicular lymphoma. These complete responses are quite durable. We have to take into account that follicular lymphoma is very heterogeneous, and we have today a range of options besides chemotherapy. But during clinical course, at third or forth treatment line, there are no standard choices and many patients develop resistance to chemotherapy. At this stage they need an alternative mechanism of action, and bispecifics can be an attractive option. We are not sure, neither in diffuse large B-cell lymphoma nor in follicular lymphoma, that they will be curative. We have not yet seen a plateau in survival curves, but with further follow-up we might better understand the curative potential of these drugs.Also, they have some advantages. We tend to compare their results to the results with CAR T-cells. The mechanism of action is not that different but common toxicities are less frequent. The complexity of the treatment with bispecifics is also lower, they are an off-the-shelf medication that do not require lymphodepletion nor waiting for manufacturing. For patients who cannot really wait, this might be a more attractive option. Maybe in the future, when we learn more about the effectiveness of CAR T-cells after bispecifics, they may be used as a bridge for CAR Ts. However the data about this sequence of treatment is still very limited. For the time being, it seems preferably to do the opposite - to first use CAR T-cells in patients who are candidates and have access (access to CAR-T is not uniform everywhere), and then salvage the patient with bispecifics if needed. We also have interesting trials using bispecifics as maintenance after CAR-Ts in aggressive lymphomas.
《肿瘤瞭望-血液时讯》:BsAbs虽然为B-NHL患者带来了希望，但其应用过程中的挑战和管理需求也相应增加。这要求医疗人员具备哪些安全性方面的应对处理能力，以确保治疗的效果和患者的安全？
Da Silva教授：所有的抗肿瘤治疗方案，我们医护人员都需要了解其治疗相关的毒性，并接受相关的管理培训。这对于一个擅长CAR-T细胞的医疗中心来说是比较容易的，因为BsAbs的毒性相似，并且程度要低得多。例如，BsAbs引起的细胞因子释放综合征（CRS）通常是低级别的。
同时，由于肿瘤患者接受的是一种长期的治疗，为了减轻一些大型医疗中心的就诊压力，也让更多的患者能够接受治疗，我们也在考虑制订一些患者管理策略，与基层的治疗中心合作并达成协议，让患者平时能够就近接受治疗周期以外的一般性治疗，然后患者定时返回至上级医院继续接受周期性的抗体给药。这也是一个非常好的建议。
最后，每位患者都应该接受相关培训，学会如何预防、及早发现最常见的急性不良反应。例如，临床上比较常见、也是所有抗肿瘤治疗都可能带来的感染问题，患者需要意识到感染的风险；少数患者可能会有神经毒性（在数量或严重程度方面不是很显著）；此外，我们还可能出现细胞减少，这可以使用生长因子来处理；还有低丙种球蛋白血症，可以通过给予免疫球蛋白来支持；有时会出现肿瘤溶解和输注反应等等。
As for all treatments, the health staff needs to learn about toxicities and get trained and experienced with these treatments. I would say it is quite easy for a center that is used to administering CAR T-cells, because toxicities are similar but at a much lower range. We see cytokine releasing syndrome (usually low grade), and we need to know how to treat manage it, because it can become serious if we don’t treat it in the beginning. We have some mitigation strategies, but they might not be entirely effective. So we need to know how to deal with it. Sometimes, we need to admit patients, although we do our best to do most of the treatment as outpatients. This is a prolonged treatment, so we really prefer to develop strategies of training the patients, the physicians and the caregivers to be able to administer as much of the treatment as possible as outpatients. Since not all these treatments are available everywhere, people are thinking about strategies where less experienced centers might be able to get into an arrangement with bigger centers, where patients can receive their first one to two cycles and then go back to their original hospital to continue the antibody administration. I think that would be a very good idea. In the end, everyone will learn how to deal with the most common acute toxicities. What I don’t know yet in detail are the delayed toxicities. I would say that the immune suppression that we are inducing, not only with bispecifics, but with all the treatments we are giving our patients, brings additional important problems, mainly infections. We need to be aware of the risk of infection in these patients, and in the future, develop better prevention and treatment strategies. For the time being though, we need to be very much aware of these risks and to suspect infection early. These are not the only toxicities we have with bispecifics, but I was focusing on the things I think concern most of us to a large degree. We have other concerns: a small numbers of patients will have neurotoxicities (not very significant in terms of numbers or severity); we see cytopenias, which we can deal with using growth factors; we have hypogammaglobulinemia, that we can support by administering immunoglobulins; we sometimes have tumor lysis and infusion reactions.
《肿瘤瞭望-血液时讯》:随着治疗的进行，患者是否会发展出对BsAbs的耐药性？未来，我们又将如何应对这一挑战？
Da Silva教授：目前，已经有研究小组正在致力于阐明对BsAbs产生耐药性的相关机制研究，这也是我们首先需要深入了解的问题。同时，还有其他针对B细胞中不同靶标的双特异性抗体正在研发当中；也有关于与BsAbs联合方案的探索，包括BsAbs和其他药物的联合，无论是化疗，还是免疫调节剂，希望能够增强患者的持久应答。除此之外，关于何时干预的问题，目前我们了解到，当T细胞消耗较少时，更早地治疗患者可能会降低患者的耐药率；此外，可以尝试在有限的时间内进行治疗，在患者病情缓解时停止使用，当患者复发或进展时再恢复治疗。这也可能是一种策略，目前正在进行这方面的临床试验。
There are groups of investigators working to clarify the mechanisms of resistance to bispecifics. The first thing we need to know is the mechanism of resistance, because if we are using an anti-CD3/CD20 antibody, and the patient loses CD20 from the tumor cells, this type of antibodies will not be effective. There are other bispecific antibodies in development against different targets in B-cells. There are also combinations with other bispecifics that act as immune stimulators. Many combinations including bispecifics and other agents, either chemotherapy or more interestingly, immunostimulators, are being developed and may be able to increase durable responses. Additionally treating patients earlier, when T cells are less exhausted may reduce the probability of developing resistance. Also, it is possibly important to have treatment over a limited period of time. If effective, it can stopped while the patient is in remission. In some trials, patients are allowed to resume treatment if they relapse or progress. That can also be a strategy. If they don’t develop resistance, we might be able to use the same agent, or a similar one, more than once.